Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme serving for catalyzing the synthesis of cholesteryl ester from cholesterol, playing an important role in the metabolism of cholesterol and intake of cholesterol in the digestive organs.
In recent years, it has been clarified that when the activity of ACAT present in the small intestine or the liver is suppressed, elevation of blood cholesterol can be effectively prevented, and a number of studies have heretofore been undertaken regarding ACAT inhibitors.
The present inventors focused on ACAT in vascular wall and studied on the selective inhibitors against this type of ACAT, thus leading to the finding that azole compounds having a cyclic diamine structure, particularly cyclic diamine derivatives of formula (5′):
(wherein A denotes NH, an oxygen atom or a sulfur atom, Wa to Wd denote CH or any one of the Wa to Wd denotes a nitrogen atom, Ra denotes a lower alkylthio group, a lower alkoxy or halo-lower alkoxy group, a lower alkoxy lower alkoxy group, each of Rb, Rc, and Rd denotes a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxy carbonyl group, a halo-lower alkyl group, a halo-lower alkoxy group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a lower alkylcarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a nitro group, or a cyano group, m is 1 or 2, and n is an integer of 1 to 6) or salts thereof exhibit reduced side effects, high water-solubility, and excellent oral absorption property and thus are useful as a remedy for hyperlipidemia and arteriosclerosis. As a result, the present inventors filed a PCT patent application (see W098/54153 pamphlet).
That patent application discloses a process for preparing cyclic diamine derivatives (5′) through the below-described production process 1 (Example 24) or the below-described production process 2 (Example 88). However, there have still been problems in such processes. For example, the following problems are noted: 1) production process 1 requires many steps because of protection and deprotection for an amino group of a piperazine ring; 2) production process 1, and production process 2 which does not use the protective group, have difficulty of synthesizing a cyclic diamine derivative (5′) in which the substituent (Ra) on the pyridine ring is mono- or di-lower alkyl amino group or a cyclic amino group; and 3) the chlorine atoms in compound (7b) are so highly reactive that the compound substituted by a methoxy group at the 4-position thereof is undesirably produced as a by-product in the reaction process performed in methanol for introducing a lower alkylthio group, and its removal is extremely difficult.
